Introduction to the protein folding problem

Recently (read: this week), I had to give a presentation on my research to my college. We were informed that the audience would be non-specialist, which in fact turned out to be an understatement. For example, my presentation followed on from a discussion of the differences in the education systems of North and South Korea for the period 1949-1960. Luckily, I had tailored my entire talk to be understandable by all and devoid of all Jargon. I choose to deviate from the prescribed topic and Instead of talking about my research specifically, I choose to discuss the protein folding problem in general. Below you’ll find the script I wrote, which I feel gives a good introduction to the core problem of this field.

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The protein folding problem is one of the great projects within the life sciences. Studied by vast numbers of great scientists over the last half century, with backgrounds including chemistry, physics, maths and biology, all were beaten by the sheer complexity of the problem. As a community we still have only scraped the surface with regards to solving it. While I could, like many of you here, go into my own research in great detail and bore you wholeheartedly for the next 10 minutes with technical details and cryptic terminology, I will instead try to give an overview of the problem and why thousands of scientists around the globe are still working on cracking this.

First of all, I guess that a few of you are trying to remind yourself what a protein is; the horror that is high school biology crawling back from that area in your brain you keep for traumatic experiences like family gatherings. Luckily, I’m fairly new to the topic myself, my background being in physics and chemistry, so hopefully my explanation will be still in the naive terms that I use to explain the core concepts to myself. Proteins are the micro-machines of your body, the cogs that keep the wheels turning, the screws that hold the pieces together and the pieces themselves. Proteins run nearly all aspects of your body and biochemistry, your immune system, your digestion and your heart beating. There are approximately between 20 to 30 thousand different proteins in your body, depending on who you ask, and trillions overall. In fact, if we take every protein in our body and scale it up to the size of a penny, the proteins in a single human, albeit a rather dead human, would be enough to fill the entire pacific ocean. Basically, there is a hell of a lot of proteins, with a vast range of different types, each of which is very individual, both in its compositions and function, and, crucially, they are nearly all essential. The loss of any protein can lead to dramatic consequences including heart disease, cancer, and even death.

So now that you know that they are important and there are lots of them, what exactly is a protein? The easiest analogy I have is that of a pearl necklace, a long string of beads in a chain. Now consider your significant other has gone slightly insane and instead of purchasing jewelry for you that consists of a single bead type, or even two if you have slightly exotic tastes, they have been shopping at one of the jewellery stores found in the part of town that smells rather “herby”. You receive a necklace which has different beads across the entire length of the necklace. We have blues, yellows, pinks, and so on and so forth. In fact, we have 20 different types of beads, each with its own colour. This is basically a protein chain: each of the beads represents one of the twenty essential amino acids, each of which has its own chemical and physical properties. Now suppose you can string those pearls together in any order: red, green, blue, blue, pink etc. It turns out that the specific order that these beads are arranged along the length of the protein chain define exactly how this chain “crumples” into a 3D shape. If you think that adding an extra dimension is impossible, just consider crumpling a piece of paper; that is 2D –> 3D transition (mathematicians please bite your tongue). Now one string of colours, blue, blue, pink for example, will crunch into one shape, and that shape may become your muscle, while a different sequence, say, green, blue, orange, will crumple down into something different, for example an antibody to patrol your blood stream.

So essentially we have this “genetic code”, the sequence of amino acids (or beads), which in turn defines the shape that the protein will take. We in fact know that it is this shape that is the most important aspect of any protein, this having been found to define the protein’s actual function. This is because, returning to the bead analogy, we can change up to 80% of the beads to different colour while still retaining the same shape and function. This is amazing when you consider how many other objects can have their baseline composition changed to the same extent while still retaining the same function. The humble sausage is one of those objects (actually below 40% meat content they are referred to as “bangers”), but even then would you want 80% of you sausage to be filler. There is a reason Tesco value sausages taste so different to the nice ones you buy at the butchers. Returning to proteins, we are not trying to say that the sequence isn’t important, sometimes changing just a single bead can lead to a completely different shape. Instead it says that the shape is the critical aspect which defines the function. To summarise, sequence leads to shape, which in turn leads to function.

This is unfortunate, because while it is getting increasingly simple to experimentally determine the sequence of a protein, that is the exact order of coloured beads, the cost and time of getting the corresponding structure (shape) is still extremely prohibitive. In fact, we can look at two of the major respective databases, the PDB, which contains all known proteins structures, and GENBANK, which contains all known protein sequences, and compare the respective number of entries. The disparity between the two is huge, we are talking orders of magnitude huge, 10^15 huge, i.e the number of humans on the planet squared huge. AND this gap is growing larger every year. Basically, people in the last few years have suddenly gained access to cheap and fast tools to get a protein’s sequence, to the extent that people are widely taking scoops of water across the world and sequencing everything, not even bothering to separate the cells and microorganisms beforehand. Nothing analogous exists to get the structure of a protein. The process taking months to years, depending on many factors, each of which may be “something” for one protein and then a completely different “something” for a similar protein. This has led to a scenario where we know the sequence of every protein in the human genome, yet we only know the structure of only about 10% of them. This is utterly preposterous in my opinion given how important this information is to us! We basically don’t know what 90% of our DNA does!

Basically, until an analogous method for structure determination is produced, we have no choice but to turn to predictive methods to suggest the function of proteins that we do not have the structure for. This is important as it allows us, to some degree, target proteins that we “think” may have an important effect. If we didn’t do this, we simply would be searching for needles in haystacks. This is where my research, and that of my group, kicks in. We attempt to take these sequences, these string of beads, and predict the shape that they produce. Unfortunately, the scientific community as a whole still relatively sucks at this. Currently, we are only successful in predicting structures for very small proteins, and when anything more complex is attempted, we, in general, fail utterly miserably. In my opinion, this is because the human body is by far the most complex system on the planet and so far we have tried to simply supplant physics on top of the problem. This has failed miserably due to the sheer complexity and multitude of factors involved. Physics has mostly nice vacuums and pleasant equations, however ask a physicist about a many body system and they will cry. So many factors are involved that we must integrate them altogether which is why there are so many people are working on this, and will be for many years to come. Well, I guess that’s good news for my future academic career.

Anyway, I hope this talk has given you some degree of insight into the work I do and you have learned something about how your body works. For those extremely interested, please feel free to approach me later and I will happily regale you with the exact aspect of protein folding I work on. But for now I would love to try and answer any questions you all have on the content contained in this talk.

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